GB1591120A - Derivatives of a-amino benzimidazole-5-propanoic acid their preparation and compositions containing them - Google Patents

Description

P-ATEN-T SP-ECI-I-CA-TION - m -1 591 120

( 21) Application No 52306/77 ( 22) Filed 15 Dec 1977 ( 31) Convenition Application No 769802 ( 32) Filed 17 F eb.

1 C1) _', 1 1)"_ l 2 ( 33) United States of America (US),( 44) Complete Specification Published 17 Jun 1981 ( 51) INT CL 3 C 7 D 235/04 A 61 K, 31/415 If CO 7 C 101/447 103/375 i ( 52) Index at Acceptance C 2 C 1416 213 220 252 25 Y 271 :30 Y, 321 32 Y 364 365 366 591 592: 597.

625-628 62 X X 660 661 KNKY LR 227 281 332 367 602 630 672 LW 22 Y 247 282 29 X 1342 34 Y 368 -36 Y 620 621 638 63 X 682 802 LZ 250 29 Y 305 > i 351 352 509 ' 50 Y 623 624 650 658 Y AA ( 72) Inventors: CHANDRAVADAN NANALAL TALATY JEREMY WRIGHT NICOLAS ZENKER l i r ( 54) DERIVATIVES OF a-AMINOBENZIMIDAZOLE-5-1 PROPANOIC ACID, THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM ( 71)' We, 'MERCK & CO INC, a corporation duly organized and existing under the laws' of thd&St;fe of New Jersey, Ilflited States bf Ameica,"of' Rah'kay; Ne'w ersey, Unite 'Stdtfe 6 f Ainericd' 'd 6 'hereby dleffire the-invention fort vhicliw'e"""piy that a ptent'may be grnintd tous and the'method by which-it is'to beperformied tobe 3 'pitticuilarly'described in and by the following statement:-

The present applicatiffi ptdi'idesg def'in'f'iino'v-el substituted benzimidazolylalanines, which ar useful las: aiitihypertefisiv' ag'ents' 3 Unsuibstittute'd' 3 (benz:imidazol-55-yl)-,alaninie ariid 3 "biziii 15-lfdhl'hn arkfs Jha 1 b Mdcih I C nir Y 44 P f 97 'Fft Wntatidf Coiigress oihr 6 dg;Abstract 96,4,'Jdfy 23-28,i 9 19723 Eacdh bf'ths&aldniiies is known to effect in W'ivo depletidn of 1 iiorepinephiine in -the brain and heart ' Neither of these 'alan ines is kndwn to' have substantial antihpertensive activity.

3,4-Dihydroxyphenyl-2-mcethyldlanuiiih',, also commonly known as methyldopa, is a well known antihypertenisive agent It also is known to effect a substantial depletion of norepinepherine, in vivo, in both the brain and heart.

The invention provides novel substituted benzimidazole alanin'es, speiifically 31 ( 6hydroxyb'enzinidazol-5-yl)alanine,' 3-'( 1 ''iyr x lytxdzmdz 15 yl)alanine and 3-( 1,3-dihydro-2-oxo-6-methoxybenzimidazol-5-yl)alanine These comnpounds, which exhibit antihypertensive activi ty, have the 'formii Ite NH 2 KN CH 2-CHCOOH <NO H HI 0 o ( 19) ,1, 1 591 120 NH 2 H NH 2 HO C H 2 CH COOH O \N C CH 2-Ct H COOH N N N I OH I OH H or its tautomer H (II) (TIA) 10 and NH 2 H NH 2 1 12 N CH 2-CH-COOH N M CH 2 CH-COOH HO-K -O CH -HC 5 / ( IL 20 'H N 15 N I OCH 3 i OCH 3 H H ( 111 A) ( ill) or its tautomer 20 The invention also provides pharmaceutically acceptable salts of such compounds Since each of the compounds of Formulae I to Illa has an asymmetric carbon atom, it is optically active Thus, these compounds include the individual optical isomers as well as the racemate and other isomer mixtures, e g mixtures of the racemate with one of the 25 corresponding optical isomers.

These individual optical isomers are variously designated as I and d, D and L, and + or by combinations of these symbols These isomers may also be designated S (sinister) and R (rectus), symbols which indicate the absolute spatial configuration of the isomer molecule.

An appropriate isomer designation may be used in naming a compound Where no 30 symbol is given, then the compound named includes the individual isomers, the racemate and all isomer mixtures.

Pharmaceutically acceptable salts include metal salts, e g those of sodium and potassium and the salts of the Formula I-Ila compound with suitable acids These acids include inorganic and organic acids Useful inorganic acids encompass the hydrohalide acids e g 35 HC 1, H Br, HI, sulfuric acid and phosphoric acid The organic acids include carboxylic and non-carboxylic acids The carboxylic acids may contain from 2 to 24 carbon atoms Useful carboxylic acids are exemplified by acetic acid, cyclohexylcarboxylic acid, maleic acid, citric acid, hexanoic acid, tetracosanoic acid, oxalic acid, succinic acid, and tartaric acid, the fatty acids e g palmitic, oleic, stearic and pamoic acids, fumaric acid, malic acid, ascorbic acid 40 and pivalic acid An especially useful non-carboxylic acid is isethionic acid Pharmaceutically acceptable means that the salts are substantially non-toxic and retain the required pharmaceutical activity.

Preferred salts are the hydrohalides and especially the hydrochlorides and hydrobromides 45 Representative salts of the compounds of Formulae I, II and III have been found to effect a reduction in blood pressure when administered to spontaneously hypertensive rats It is believed that the compounds of the present invention are useful to treat hypertension in animals, including humans Hypertension manifests itself, and is commonly referred to, as "high blood pressure" Thus, the present compounds are useful in lowering the blood 50 pressure of hypertensive patients.

A representative salt of the Formula I compound has also been found to reduce norepinephrine in the brain and heart of rats using a conventional test procedure.

The dosage required to effect lowering of blood pressure in the hypertensive patient will vary Daily dosage ranging from 10 to 3500 mg of a compound of Formula I to M Ila is useful 55 A preferred daily dosage range is 50-1000 mg, with 100-750 mg being more preferred.

The compounds may be administered alone or in combination with suitable pharmaceutical compounding ingredients Useful dosage forms include those suitable for oral administration e g tablets, capsules, suspensions and emulsions, as well as for parenteral administration e g solution, suspension and emulsion The dosage forms are prepared 60 using conventional procedures, equipment and compounding ingredients e g diluents, carriers, excipients and encapsulating materials.

In addition to the more conventional administration modes and dosage forms, the present compounds may also be administered in a form that will dispense the compound to the patient continuously over an extended period of time This method of administration is 65 3 1 591 120 3 embodied in a carrier device or means which is imbedded, inserted, attached, ingested or otherwise provided to the patient An advantage of this form of administration is that it ensures continuous, regulated and convenient administration of the hypertensive agent to the patient.

The following examples illustrates preparation of a representative compounds of the 5 present invention While the example products obtained are racemates (D, L) , they may be separated into the D and L enantiomers by conventional procedures such as resolution using an optically active acid (e g tartaric acid) in a suitable solvent system All temperatures in the example are in degrees centigrade; "Celite" and "Novit" are trade marks 10 EXAMPLE 1

Preparation of D, L-3-( 6-hydroxybenzimidazole-5-yl)alanine 2 H Br A Diethyl a-( 2-methoxy-5-nitrobenzyl)-ca-acetamidomalonate 15 15 OCH 3 COO Et OCH 3 COO Et J Cl + HC NH Ac Na O Et/Eto H -NH Ac 20 I 5 Hours COO Et ref lux COO Et NO 2 NO 2 25 Molar amounts of 2-chloromethyl-4-nitroanisole and freshly prepared diethyl sodioacetamidomalonate were refluxed in ethanol for 5 hrs and the turbid solution filtered hot The filtrate was allowed to cool and re-filtered to yield diethyl a-( 2methoxy-5-nitrobenzyl)-ctacetamidomalonate A in 70 75 % crude yield, m p 161 163 This crude product was used 30 for the next step as such.

B Diethyl a-( 2-methoxy-5-acetylaminobenzyl)-a-acetamidomalonate OCH 3 OCH 35 OCH 3 COO Et a C 3 COO Et N Pd/C H 2 H Ac NH Ac Et OH > NH Ac > / COO Et COO Et 2 40 NO 2 NH 2 A Amine 45 OCH 3 1-.3 COO Et -h H Ac 5 COO Et NH Ac 55 B The crude nitro compound A ( 15 g) from the previous step was dissolved in absolute ethanol ( 200 ml), Pd-C ( 10 %, O 8 g) was added and the mixture was hydrogenated in a Paar 60 bottle at 40 psi until no more hydrogen was absorbed ( 2-3 hrs) The mixture was filtered through Celite (to remove Pd-C) and the filtrate evaporated in vacuo to give the colorless solid amine m p 129-131 The amine was in all cases directly acetylated by refluxing with acetic acid ( 5 ml) and acetic anhydride ( 25 ml) for 1 hour The mixture was then poured into ice water ( 100 ml), cooled in the refrigerator for 1 hour, and filtered The solid was then 65 4 1 591 120 4 washed with water Drying in vacuo at 60 yielded 13 5 g of the desired acetate B ( 88 %), mp 143-145 The crude acetate B was taken up for nitration without further purification.

Recrystallization from ethyl acetate yielded an analytical sample of B mp 150-51 .

C Diethyl a ( 2-methoxy-4-nitro-S-acetamidobenzyl)-a-acetamidomalonate OCH 3 COO Et OCH 3 COO Et l Conc HN 03 10 NH Ac + H Ac + Ac 20) NH Ac N COO Et 02 N COO Et NH Ac B NH Ac C The crude acetate B from the previous step ( 15 g) was stirred in a 250 ml 3-necked flask 20 with a 1:1 by volume mixture of acetic acid and acetic anhydride ( 45 ml) The solution was cooled externally in ice to 0-5 Through a dropping funnel, conc HNO 3 ( 30 ml) was gradually added while the temperature was maintained below 10 (l Hr) After being stirred for an additional 1 hour at 10-15 , the reaction mixture was gradually added with rapid stirring to Na HCO 3 ( 120 g) in 400 ml cold water to bring it to p H 7 The mixture was stirred 25 for 30 minutes, filtered and washed with water to give 18-20 g of a darkyellow solid, mp 157-158 Recrystallization from CHC 13:Hexane ( 1:1, 200 ml) yielded 14 7 g ( 88 %) of crystalline yellow compound C, mp 159-161 .

30 D 2-Methoxy-5-amino-4-nitrophenylalanine OCH 3 COO Et OCH 3 1 SNHCl NH 40 H 35 a\ NH Ac > 3 4 COOH Rettux 6 p H 6 /COOE Hours H 2 02 N | COQ Et NO 2 N 2 40 NH Ac NH 2 C D 45 Compound C (O 10 g) was refluxed with 5 N HCI ( 90 ml) for 6 hours The solution was then cooled in ice and neutralized with 30 % NH 4 OH to p H 6, cooled in the refrigerator overnight, filtered and dried in a vacuum oven, or at room temperature, yielding 5 5 g of the crude compound D, mp 2320-234 However, the compound contained 1 mol of water of 50 crystallization The yield as hydrate was 88 % The amino acid D was directly used without further purification in most cases A small amount of the sample was recrystallized from CH 3 OH:H 20 ( 1:1) giving bright-red crystals of the hydrate of D m p 239 -240 (dec), (color changing to pale-yellow around 110 ).

1 591 120 E 3-l 5 ( 6)-Methoxy-benzimidazol-6 ( 5)-yllalanine HCI COOH NH 2 % Pd-C N H Cl NH 2 D OCH 3 COOH NH 2 H 2 N I 2-3 H Clt NH 2 / CH 3 NH 2 2 H Ct 0 11 II H C -OH N HCI E The crude amino acid D ( 1 0 g) was dissolved in SN H Cl ( 40 ml) in a Paar bottle, 5 % Pd-C ( 0 1 g) was added and the mixture hydrogenated ( 1 5-2 hours) at 3540 psi until no additional H 2 was absorbed The Paar Bottle was then flushed with N 2 and the contents transferred to a 250 ml flask containing 7 ml formic acid ( 97 %) and 5 ml of SN HCI The mixture was refluxed for 3 5 hours with exclusion of air (Hg trap used) and was then stirred ( 30 minutes) with Norit (a charcoal) and filtered through Celite to give a pale-yellow mother liquor The solvent was then removed in vacuo and the solid obtained was co-evaporated in vacuo twice with 5 ml isopropyl alcohol each time (to remove excess of H-COOH and H Cl) Finally isopropyl alcohol was added and the mixture refrigerated overnight The solid was then filtered, washed well with cold isopropyl alcohol, and dried at and 0 1 mm Hg for 5 hours giving 970 mg of a pale-yellow solid, mp 271 (dec) which was recrystallized from ethanol:water and dried in vacuo to give 620 mg ( 51 1 %) of compound E, mp 275 (dec).

S 02 N 1 591 120 F D,L-3 ( 6-dihydroxybenzimidazol-5-yl) alanine 2 HBR OCH 3 OH COOH N T II NH NH 2 .2 HCL 48 % H Br 6.5 Hrs Reflux COOH > 2 H B r The amino acid E ( 1 35 g) was refluxed with 48 % H Br ( 25 ml) for 6 5 hours using a Hg trap to exclude air The solution was cooled in a freezer overnight The solid that separated on cooling was filtered, washed first with acetone and then with ether On drying the solid in vacuo at 110 , crude compound F ( 1 6 g), decomposing at 279 , was obtained The solid was dissolved in ethanol:H 20 ( 45:5 ml) and treated with neutral Norit (a charcoal) for 4 hours After filtering through Celite to remove charcoal, the mother liquor was evaporated in vacuo and the solid recrystallized from ethanol:acetonitrile ( 1:2) to yield 0 9 g ( 53 6 %) of colorless product F, decomposing at 273 .

EXAMPLE 2

Preparation of D,L-3-( 1,3-dihydro-2-oxo 6-hydroxybenzimidazol-5-yl)alanine H Br A 3-( 1,3-dihydro-2-oxo 6-methoxybenzimidazol-5-yl)alanine OCH 3 COOH 02 N NH 2 % Pd-C N HCI D OC H 3 COOH H 2 N 2 -3 / 0 11 II Ct C Cl N H Cl COOH HCI HN | > NH U G The crude amino acid D ( 2 5 g) was dissolved in 5 N HCI ( 175 ml), 5 % Pd-C ( 0 25 g) was added and the mixture was hydrogenated at 35-40 psi until no more H 2 was absorbed ( 1 57 1 591 120 7 2 hrs) The Paar bottle was flushed with N 2 and the contents trasferred to a 3-necked flask; phosgene gas was passed through the solution for one hour and the solution was then heated for 30 min on a steam bath The solid which precipitated during the reaction was collected on a Buchner funnel and the mother liquor evaporated in vacuo to give additional product The combined solids (containing Pd-C) were carefully dissolved in ethanol ( 25 ml) 5 and water ( 10 ml) and stirred with Norit for about 1 hr Filtration through Celite and concentration in vacuo yielded an almost colorless solid, ( 1 1 g) Recrystallization from ethanol:water ( 5:1) yielded 0 85 g ( 32 3 %) of the desired product G mp 2880 (dec).

B D,L-3-( 1,3-dihydro-2-oxo 6-hydroxybenzimidazol-5-yl)alanine H Br 10 OCH 3 OH COOH 8 / COOH 15 481 /o H 2 r H 2 NH NH | 6 5 Hrs reflux HN HN NH NH HB 20 O H Ct G ILL 25 The amino acid G ( 0 600 g) was refluxed with 48 % H Br ( 23 ml) for 6 5 hrs using a Hg trap to exclude air The solution was then evaporated in vacuo and the solid was dissolved in CH 3 OH ( 40 ml) and treated with Norit for 1 hr After filtering through Celite, the mother liquor was concentrated in vacuo to give a solid The solid was recrystallized from CH 3 OH:CH 3 CN ( 1:2) to yield 432 mg ( 65 %) of a colorless, solid compound H mp 268 30 (dec).

The G and H compounds also include their tautomers.

HI can be used in place of H Br to effect the ether cleavage in Example 1, step F, or Example 2, step B and the resultant product will then be the HI salt.

The benzimidazole alanine product in Example 1, Step F or Example 2, step B is 35 obtained as the H Br or HI salt This salt may be conventionally neutralized to provide the free alanine base The base can then be used as such as an antihypertensive agent or converted to any other suitable salt by treatment with appropriate acid or base.

Claims (1)

1. WHAT WE CLAIM IS:

   1 A compound having the formula: 40 NH 2 NH 2 N < CH 2-CH-COOHHo<N H 2-CHCOOH 45 N N I OH OH H H (I) (II)50 or H NH 2 55 I 5 N CH 2-CH-COOH KN OH H 60 (h IA) including its tautomers, or a pharmaceutically acceptable salt thereof.

   8 1 591 120 8 2 A compound as claimed in Claim 1 in DL racemic form.

   3 HCI, H Br, and HI salts as claimed in Claim 1 or 2.

   4 DL-3-( 6-hydroxybenzimidazol-5-yl)alanine dihydrobromide.

   DL-3-( 2,6-dihydroxybenzimidazol-5-yl)alanine monohydrobromide.

   6 DL-3-( 1,3-dihydro-2-oxo-6-methoxybenzimidazol-5-yl)alanine monohydrochloride.

   7 A compound having the formula:

   NH 2 N 10 LCH 2-CH-COOH <N OCH 3 I H 15 (IA) or a hydrohalide salt thereof.

   8 A method of preparing a compound having the formula (I) in Claim 1, that comprises 20 cleaving the -OCH 3 group in a compound having the formula:

   NH 2 I 25 N lMCH 2-CH-COOH <N OCH 3 H 30 (IA) 9 A method as claimed in Claim 8 effected by treating the compound of formula IA with H Br 35 A method of preparing a compound having the formula:

   NH 2 I 40 H 40N CH 2-CH-COOH 40 " 0-N I OH H 45 (II) which comprises cleaving the -OCH 3 group in a compound having the formula:

   H NH 2 I I =< N j CH 2-CH-COOH I OH H (IIA) 1 591 120 A 9 1 591 120 Q 11 A method as claimed in Claim 10 effected by treating the compound of formula IIA with H Br.

   12 A method of preparing a compound having the formula:

   5 H NH 2 I I 0 =,< NCH 2-CH -COOH N 10 I OCH 3 H ( 1111 15 that comprises (a) hydrogenating a compound having the formula NH 2 20 H 2 N CH 2 LHCOOH 02 N i s OCH 3 25 and (b) treating the product from (a) with phosgene.

   13 A method as claimed in Claim 12 in which the hydrogenation is effected using 30 hydrogen in the presence of a Pd-on-charcoal catalyst.

   14 A method of preparing a compound as claimed in Claim 1 substantially as hereinbefore described in Example 1 or 2.

   A compound as claimed in Claim 1 when prepared by a method as claimed in any one of Claims 8 to 14 35 16 A pharmaceutical composition for treating hypertension containing a compound as claimed in Claim 1 together with a suitable pharmaceutical compounding ingredient.

   17 A composition as claimed in Claim 16 in the form of a tablet, capsule, suspension or emulsion.

   40 For the Applicants, D YOUNG & CO, Chartered Patent Agents, 9 & 10 Staple Inn, London, WC 1 V 7RD 45 Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981.

   Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

   1 591 120 Q